Patients with nephrotic syndrome frequently have suppressed clinical or in vitro immune responsiveness. The lack of significant renal morphologic changes in minimal change nephrotic syndrome has suggested that, at least in this disease, the immunologic abnormalities could in some way cause proteinuria. However, the actual nature of the immune alterations is unknown, in part becasue techniques available for exploring this problem have been limited. The overall goal of this project is to apply recently developed fundamental immunologic concepts to the study of altered immunity in nephrotic syndrome. Specifically we propose to determine whether a suppressor substance found in the urine of certain nephrotic patients is human soluble immune response suppressor (SIRS), an antigen-nonspecific lymphokine produced by activated suppressor T lymphocytes. This will be accomplished by comparing and contrasting biological, physicochemical, structural and antigenic characteristics of SIRS and suppressor substances found in urine. Preliminary data suggest that the kinetics of suppression and the ability of certain reagents to block suppression by this urine-derived substance are identical to those found in SIRS-mediated suppression. Our goal is to confirm this relationship through purification and characterization of this material and determination of the mechanism of suppression. Production of the urine suppressor substance will be evaluated in relation to onset and remission of nephrotic syndrome, as well as type of renal disease. Nephrotic patients will be tested for the presence of activated, SIRS-producing cells. In addition, the effects of therapies for nephrotic syndrome on SIRS production will be evaluated. Finally, an animal model of this disease would permit further manipulation of parameters not possible in patients. To this end SIRS, and inducers of SIRS such as interferon, will be injected into mice to determine whether (1) immune responses are suppressed, (2) SIRS can be detected in urine, (3) proteinuria is induced, and (4) any renal pathology is induced. These studies should help clarify the nature of the immune abonormalities in nephrotic syndrome and may further our understanding of their possible role in mediating renal disease.